The serotonin 5-HT2C receptor, one of the receptors of the biological transmitter serotonin, is distributed mainly in the central nervous system and controls many physiological functions in vivo. A representative example is the control of appetite; it has been demonstrated in a study with rodents that when the central serotonin 5-HT2C receptor is stimulated, eating behavior lessons and body weight is lost. In humans as well, it has been reported that when a serotonin 5-HT2C receptor activator is administered, appetite is suppressed and body weight is lost (see non-patent document 1). In addition, stimulation of the central serotonin 5-HT2C receptor has been shown to suppress depression-related behavior in a rat study using a serotonin 5-HT2C receptor activator (see non-patent document 2), and has also been reported to be effective on many central nervous diseases such as anxiety (see non-patent document 3). The serotonin 5-HT2C receptor is also highly expressed in the parasympathetic nucleus and motorial nerve cell bodies in the sacral spinal cord, and is thought to control peripheral nervous functions (see non-patent document 4). It has been reported that when a serotonin 5-HT2C receptor activator is administered to rats, penile erection is induced (see non-patent document 5), and urethral resistance is increased (see patent document 1); all these actions are attributed to stimulation of the serotonin 5-HT2C receptor in the sacral spinal cord. For serotonin 5-HT2C receptor activators, many clinical applications are likely, with particular expectations for anti-obesity drugs, antidepressants, anti-anxiety drugs, therapeutic drugs for male erectile dysfunction, and therapeutic drugs for stress urinary incontinence and the like.
As a heterocyclic amine compound, the following compounds have been reported.
(1) A compound represented by the formula
wherein ring Ac is an optionally substituted aromatic ring; ring Bc is a nitrogen-containing 6- to 9-membered ring optionally further having substituent(s) other than -Lc-Rc; Xc is an optionally substituted methylene group; Ar is an optionally substituted aromatic group; Rc is an optionally substituted cyclic group; Lc is an optionally substituted C1-3 alkylene group, —CONH—, —SO2NH— or —SO2—, and Xc is not a methylene group substituted by an oxo group, or a salt thereof (see patent document 2).(2) A compound represented by the formula
(see non-patent document 6).(3) A compound represented by the formula
(see non-patent document 7).(4) A compound represented by the formula
wherein ring A is an optionally further substituted aromatic heterocycle;ring B is an optionally further substituted nitrogen-containing 6- to 9-membered ring;Xa is an optionally substituted methylene group (excluding —C(═O)—);Xb is an optionally substituted methylene group;Y is an optionally substituted C1-3 alkylene group, —CONH—, —SO2NH— or —SO2—,R is an optionally substituted aromatic group; andring D is an optionally substituted aromatic ring or an optionally substituted non-aromatic heterocycle,provided that when ring D is an optionally substituted benzene ring, then the benzene ring has a substituent at the ortho-position relative to the bond with ring A, or Xb is a substituted methylene group,or a salt thereof (see patent document 3).
However, no reference is made to the serotonin 5-HT2C receptor-activating action of the compound.
“Pelvic organ prolapse” is a disease wherein the anterior wall of the vagina, the posterior wall of the vagina, the uterus, the vaginal stump after hysterectomy or the urinary bladder descends and protrudes beyond the vaginal orifice (see, for example, non-patent document 8 and non-patent document 9); this descent becomes conspicuous when abdominal pressure rises transiently as a result of straining or bearing a heavy load and the like. “Rectal prolapse” is characterized by the symptom in which the rectum likewise descends and protrudes beyond the anus (see, for example, non-patent document 8). These diseases are prevalent in females, with childbirth, aging, and obesity being known as risk factors, and one of suggested causes thereof is the weakening of the pelvic floor muscles and perivisceral connective tissue that support the vagina, the uterus and the like. The pelvic floor muscles are skeletal muscles that unite with the pelvis in a hammock-like way, serving constantly to maintain some contraction and support the organs in the pelvis from below. In pelvic organ prolapse and rectal prolapse, organ weights reportedly become unendurable because of the weakening of these pelvic floor muscles, resulting in the descent of the pelvic organs and the rectum (see, for example, non-patent document 8 and non-patent document 9); it is thought that when abdominal pressure rises particularly, the increased pressure becomes unendurable and the protrusion becomes more conspicuous. On the other hand, it has been reported that when abdominal pressure rises, the urinary bladder is compressed, reflex via the urinary bladder-spinal cord-pelvic floor muscles and the urethra causes the pelvic floor muscles and the urethral sphincter to contract to increase urethral internal pressure, whereby urinary incontinence is prevented (see, for example, non-patent document 10). For this reason, it is thought that upon a rise in abdominal pressure, the pelvic floor muscles contract reflexly to prevent not only urinary incontinence, but also the descent of the pelvic organs. If there is a disorder in this reflex pathway or the pelvic floor muscles, sufficient contraction of the pelvic floor muscles cannot be obtained and support for the pelvic organs becomes inadequate. Therefore, in screening for a therapeutic drug for pelvic organ prolapse or rectal prolapse, a test system for evaluating the contractile responses of the pelvic floor muscles is useful. However, almost no basic studies have been conducted on these prolapses (pelvic organ prolapse and rectal prolapse), and currently there is no evaluation system. Nor is there any reported method of evaluating the contractile force of the pelvic floor muscles in vivo.
Lower urinary tract symptoms consist of storage symptoms, voiding symptoms and post-micturition symptoms, and one of the major post-micturition symptoms is post-micturition dribble. Post-micturition dribble is a complaint of involuntary voiding immediately after micturition, occurring usually after leaving the toilet bowl for males, and after standing up for females. For post-micturition dribble as such, it has been reported that pelvic floor muscle exercise is effective (see non-patent documents 11 to 13); the weakening of the pelvic floor muscles is thought to be a cause thereof.
Many compounds are known to bind to the serotonin 5-HT2C receptor; patent documents 4 to 9 state that compounds that bind to the serotonin 5-HT2C receptor are useful in the treatment of stress urinary incontinence and the like, but there is no statement on their therapeutic effects on pelvic organ prolapse, rectal prolapse or post-micturition dribble.    non-patent document 1: Expert Opinion on Investigational Drugs, 2006, vol. 15, p. 257-266    non-patent document 2: J. Pharmacol. Exp. Ther., 1998, vol. 286, p. 913-924    non-patent document 3: Pharmacology Biochemistry Behavior, 2002, vol. 71, p. 533-554    non-patent document 4: Neuroscience, 1999, vol. 92, p. 1523-1537    non-patent document 5: Eur. J. Pharmacol., 2004, vol. 483, p. 37-43    non-patent document 6: Chemiker-Zeitung, 1991, vol. 115, No. 12, p. 367-369    non-patent document 7: Chem. Pharm. Bull., 1977, vol. 25, No. 6, p. 1443-1446    non-patent document 8: Lancet 2007, vol. 369, p. 1027-38    non-patent document 9: European Urology 2007, vol. 51, p. 884-886    non-patent document 10: American Journal of Physiology Renal Physiology 2004, vol. 287, p. F434-441    non-patent document 11: British Journal of Urology 1997, vol. 79, p. 892-897    non-patent document 12: Urologic Nursing 2004, vol. 24, p. 490-497, 512    non-patent document 13: British Journal of Nursing 2005, vol. 14, p. 1014-1018, 1020-1021    patent document 1: WO04/096196    patent document 2: WO04/067008    patent document 3: JP-A-2006-056881    patent document 4: WO02/040457    patent document 5: WO02/083863    patent document 6: WO03/097636    patent document 7: WO04/000829    patent document 8: WO04/000830    patent document 9: WO02/008178